Project Summary/Abstract We aim to develop dual soluble epoxide hydrolase/fatty acid amide hydrolase inhibitors that will be used as a promising novel therapeutic strategy in the pain management. We will study a series of benzothiazole- phenyl piperidine analogs which exhibit potent inhibition at both targeted enzymes, and that are metabolically stable in liver microsomes. The compounds we propose to study represent a much-needed, completely novel, nonopioid, starting point in pain management research. Because this class has different biological targets from existing analgesics, it represents an opportunity to solve long-standing problems that have been linked to the existing therapies in pain management. In this project we propose that the simultaneous regulation of the two enzymes, soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH), by dual inhibitors, can be expected to play a significant role in the success of this therapeutic strategy. We know that co-administration of sEH and FAAH inhibitors significantly reduces pain in several animal models of pain. However, this promising strategy of dual inhibitors of both enzymes has not been robustly investigated as a nonopioid pain medication development approach. This novel class of nonopioid analgesics provides flexibility and an advance in the medicinal chemistry space that may overcome weaknesses in the currently available pain treatments. The most original and mechanistically distinct aspect of these compounds is their ability to simultaneously inhibit two different enzymes that play significant roles in pain and inflammation. Overall, the combination of structure- activity relationship studies and computational approaches in this proposal will enable a detailed characterization of the molecular determinants required for dual inhibition of these novel ligands. This will ultimately allow the development of potent and metabolically stable dual sEH/FAAH inhibitors. Such molecules will be valuable to study as pain management therapeutics with predictably superior clinical profiles as compared to current opioid and nonopioid drugs.